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Effect of Microflora on immune development

Immune development was studied in conventional (farm reared) and isolator (SPF) reared piglets to 28 days of age. Pairs of farrowing sows were selected from a commercial pig farm and at 24 hours, half of each litter was removed from sow and transferred to an SPF isolator.

The other half of the litter remained with the sow and the piglets were not given access to creep feed. The isolator piglets were fed a bovine-based milk replacer on an hourly-based cycle. Piglets (n=6 per group) from both experimental groups were killed at 2, 5, 12, 20 and 28 days of age. Tissue samples were collected from the small intestine, spleen and mesenteric lymph node for phenotypic analysis, by flow cytometry and immunohistology, and functional analysis, by in vitro cytokine production and cell proliferation/survival analysis.

The intestines of newborn pigs are essentially devoid of immune cells and remain so in germ free animals until the introduction of a bacterial population. In conventionally reared pigs, immune cells start to appear in the intestine within a few days. The number of cells presented represents the culmination of a number of processes including, cell emigration, cell proliferation and cell death. Cells isolated from the lamina propria of piglets raised in a SPF isolator (high hygiene) showed an increase in the relative survival of CD4+ cells from 5-12 days of age. Possibly indicating that these cells were more reactive than equivalent cells isolated form pigs reared under conventional (low hygiene) conditions.

Rearing environment had little influence on the overall numbers of CD14+, CD14+CD16+ , MHC Class II+ CD16+ and MHC Class II+ APC. However there was a significant decrease in MHC Class II expression at 20 days of age in the farm-reared piglets. The results showed that that co-localisation of both CD14+CD16+MHC II+MIL11+ and CD16+MHC II+MIL11+ events were significantly greater than predicted. In contrast the observed CD16+MIL11+ association was less that expected and there was no difference from expected for CD14+CD16+MIL11+. Taken together these results would suggest that there were significant interactions between CD16+MHC II+ and CD14+CD16+MHC II+ cells and MHC II+ and endothelium. These changes in interaction were not related to age or rearing environment.

There was a rapid increase in IL-2 production in the first few days of life and this is consistent with the rapid influx of T cells with the peak coinciding with the arrival of CD+ T cells. In contrast IL-4 production was high at all time points suggesting that a small number of T lymphocytes present in the cultures were able to produce high levels of IL-4 or that other cell types present may have been able to produce IL-4. The considerable environmental changes that the high-hygiene isolator-reared group experienced had little effect on the progress of this extensive phenotypic T cell development.

As other work has shown that germ-free animals show a total lack of immune cells in this environment and our animals shared the same farm environment and maternal colostrum during their first day of life, this early life exposure to microflora appears to be sufficient to drive the subsequent immune maturation. Parallel studies performed on samples collected from these pigs (WP 2; participant number 3) would suggest that qualitatively there were no significant differences in the intestinal microbial populations between farm and isolator reared piglets during the first 12 days of life. This would suggest that the differences observed between isolator and farm reared piglets at 5 days of age were not an effect of microbial but rather removal from the sow and change of diet. In contrast lamina propria IL-4 production was slightly reduced levels in the isolator-reared animals which might be indicative of a lack of maturity or altered Th1:Th2 balance.

The results have shown that there are significant differences in the cell populations found in the intestinal lamina propria of young (less that 28 days) as opposed to older piglets. The results strongly support the conclusion that at ages commonly used in european pig weaning practices, the piglets immune system may not be sufficiently developed to respond to the challenges of weaning. This would suggest that either a later a weaning age should be adopted or we should seek to enhance the development of the piglets' mucosal immune system.

The results rearing piglets under different hygiene conditions have supported the conclusion that this developmental process is influenced by gut microbial flora. Research programmes to develop novel immune potentiators or to provide "natural" alternatives to anti-microbials (eg FEED FOR PIG HEALTH) should provide a rational scientific basis for the formulation of future pig weaning practices.

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UNIVERSITY OF BRISTOL
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BS40 5DU BRISTOL
United Kingdom
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